DESCRIPTION: Dr. Cronstein has provided preliminary data that topical adenosine A-2 receptor agonists increase fibroblast and endothelial migration in vitro and a specific A-2a adenosine receptor agonists accelerates wound closure in healthy and diabetic rats. They propose to analyze adenosine receptor mediators to accelerate wound healing in three levels: in all animals, the cells and tissues involved in wound healing, and by examining the intracellular signaling for adenosine A-2 receptors and fibroblast endothelial cells in keratinocytes. The aims, therefore, are to: 1) study the effects of topical application of adenosine receptor agonists and antagonists on the rate of wound closure and healing in normal animals and animals lacking adenosine A-2a and A-3 receptors. The second aim is to determine whether adenosine A-2 receptor occupancy modulates cellular function important for promotion of wound healing, including matrix protein secretion, matrix metalloprotease secretion, growth factor secretion and migration, both in vitro and in vivo, in normal animals and those rendered deficient in basic fibroblast growth factor, plasminogen, urokinase plasminogen activator and tissue plasminogen activator and Tumor Necrosis Factor-alpha receptors. The third aim will be to examine signal transduction pathways for fibroblast endothelial cell and keratinocyte adenosine A-2 receptors by determining the effect of adenosine receptor activation on cellular cAMP content, PKA-mediated phosphorylation of specific signalling proteins, the activity of their downstream signalling elements, and identification of specifically phosphorylated proteins in adenosine receptor agonist-treated cells. The hope to determine a new set of pharmacologic agents that may affect tissue repair.